Preclinical and clinical studies suggest that ligands for metabotropic glutamate receptors (mGluR5) have exciting potential for treatment of a wide variety of neurological and psychiatric disorders, including depression, anxiety disorders, schizophrenia, pain, epilepsy, Alzheimer's disease, and Fragile X syndrome. Dr. Conn's laboratory and others have been highly successful in developing a novel approach to the activation of mGluR5 using highly selective positive allosteric modulators (PAMs) of this receptor. These mGluR5 potentiators do not activate the mGluR5 receptor directly, but dramatically potentiate the response to the orthosteric ligand glutamate. mGluR5 allosteric modulators have exciting potential as novel therapeutic agents and are being rapidly advanced in preclinical and early clinical drug development efforts. Recent studies in Dr. Conn's laboratory suggest that PAMs of the mGluR5 may provide a novel approach for the treatment of the psychotic symptoms and cognitive impairments observed in individuals with schizophrenia. Additionally, mGluR5 receptors have been implicated in the cognitive deficits observed in individuals with fragile X syndrome. This proposal involves determining the functional brain penetrance and in vivo efficacy of the novel selective mGluR5 PAM, VU0357040. In the initial studies, we will determine the in vivo receptor occupancy of VU0357040 via microPET imaging utilizing the radioligand [ISFJFPEB in order to understand the functional brain penetrance of this compound. Based on these occupancy studies, we will select doses and timepoints for further characterization of VU0357040 in behavioral models predictive of antipsychotic activity and enhancement of cognition. Specifically we will assess the ability of VU0357040 to reverse stimulant-induced disruptions in prepulse inhibition of the acoustic startle reflex, a model of antipsychotic efficacy and sensory gating enhancement. In addition we will assess the effects of this compound in the delayed non-matching to position task, a model of working memory. Finally, using animal models of hippocampal-dependent learning and memory, namely the Morris water maze task and contexual fear conditioning, we will evaluate the effects of this mGluR5 PAM on cognitive function in an animal model of fragile X syndrome. Ultimately, a better understanding of allosteric activation of these receptors may lead to improved therapies for patients suffering from a variety of psychiatric and neurological disorders.